MCL-509

The manufacturing route to a novel apomorphine Parkinson′s drug candidate (MCL-509) has been developed from a mg laboratory scale to that suitable for use on a 20-50 L scale.While the synthetic sequence could not be bettered, all six reaction steps required significant improvement for scale-up.Hazardous and toxic reagents and hazardous steps were removed; all concentrations to dryness and chromatog. purifications were eliminated; isolations were operationally simplified, and plant cycle times were shortened.Two pairs of steps (1 and 2; 5 and 6) were successfully telescoped, and steps 3, 4, and 5 were re-imagined such that all three steps were substantially redeveloped with alternative reagents.Now relying solely on crystallizations for isolation, the yield, purity, and color of each intermediate was greatly improved.All six process steps were easily transferred to the pilot plant with only minimal accommodation work required prior to manufacture on a 20-50 L scale per batch.Thus, the manufacturing campaign performed essentially as expected and without issues while delivering an approx. 10-fold increase in material yield alongside the requisite quality improvements.

A series of novel aporphine derivatives were synthesized for initial screening at the 5-HT₂ receptor subtypes. Among them, Compounds 11a and 11b were identified as potent 5-HT_2C hit ligands with high selectivity over other 5-HT₂ receptor subtypes. Molecular docking study revealed that compounds 11a and 11b formed two key interactions with the binding site of 5-HT_2C receptor, including a salt-bridge to D3.32 and a H-bond interaction with N6.55.